Identification of the prostanoid receptor mediating PGE2-induced cough

• Main Author: Maher, Ann
• Other Authors: Belvisi, Maria ; Birrell, Mark
• Published: Imperial College London 2009
• Subjects: 616.2
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.513462

Prostaglandin E2 (PGE2) may provide a novel therapy for the treatment of inflammatory airway diseases as it has been shown to confer both bronchodilator and anti-inflammatory activity in asthmatic subjects. However, PGE2 can cause irritancy of the upper airway resulting in a reflex cough. The aim of this thesis was to identify which of the 9 prostanoid receptors (EP1, EP2, EP3, EP4, DP, FP, IP, TP and CRTh2) mediate the PGE2-induced cough. The cough reflex is under the control of sensory afferent nerve fibres that innervate the lungs via the vagus nerve. Using an in vitro model of vagal sensory nerve depolarisation, gene and protein expression techniques and a guinea-pig cough system, I investigated the prostanoid receptor(s) responsible for the PGE2-induced depolarisation of the vagus nerve and cough. A conscious guinea-pig cough system was characterised and I confirmed that guinea-pigs, like humans, cough in response to PGE2. Isolated vagus nerves from guinea-pig, mouse and human were characterised in response to PGE2 and other tussive stimuli, capsaicin and low pH. Isolated nerves from these species behave similarly suggesting that effects observed in these small animals translate to man. It was discovered that depolarisation to PGE2 was virtually abolished in isolated vagus nerves from EP3 receptor knockout (KO) mice. This suggests that the response to PGE2 is mediated by the EP3 receptor, supported by evidence that an EP3 receptor antagonist (L826266) inhibited the response to PGE2 in isolated vagus nerves from guinea-pig, mouse and human. Expression of the EP3 receptor was confirmed in guinea-pig vagal nerve ganglia (containing the cell bodies of nerves carried in the vagus) using Taqman RT-PCR and immunohistochemical staining. Ultimately, I demonstrated the role of the EP3 receptor in vivo using a selective EP3 receptor antagonist to attenuate PGE2-induced cough. This thesis identifies the receptor responsible for PGE2-induced cough representing a key step in developing a drug that is anti-inflammatory and a bronchodilator but devoid of tussive side effects